Noninvasive imaging of small animal models has the potential to benefit every area of biomedical research for a diverse range of human conditions. High-resolution computed tomography and magnetic resonance imaging provides information down to size scales of 10 microns, but primarily are used to visualize structure and anatomy. Small animal radionuclide imaging techniques such as microSPECT and microPET imaging of physiological function and metabolic processes, but are fundamentally limited to spatial resolutions of approximately 1 mm. To overcome these limitations, this project will develop a new method to perform radionuclide imaging of intact animals at spatial resolutions approximately 5- to 10-fold better than current methods. This new approach relies on grazing incidence mirrors that reflect and focus gamma-rays to form an image without using absorptive collimation that compromises the spatial resolution and detection sensitivity of current techniques. The project therefore will test the feasibility of developing a radionuclide imaging system with 100 micron spatial resolution for visualizing function and biomolecular processes in mice using commonly available radiopharmaceuticals labeled with 1-125 or Tc-99m. The specific aims of the project are as follows: (1) Ray-tracing studies will be performed to develop optical designs that optimize the geometric efficiency for imaging the low-energy photons from Tc-99m or from 1-125, with the goal of achieving a spatial resolution of 100 microns and a 1-2 cm field of view. (2) Two prototype lenses, one designed for 1-125, another engineered for Tc-99m will be fabricated via an electroforming replication process. (3) Each lens will be configured with a Csl scintillator phosphor coupled to an electron multiplying CCD detector to characterize their optical properties (e.g., spatial resolution and sensitivity). (4) Planar phantom studies will be undertaken to determine the best methods for image reconstruction and to demonstrate its potential for microscopic gamma-ray imaging of mice. The long-term goal of this project is to develop an in vivo gamma-ray microscopy system that has 100 micron spatial resolution, high sensitivity and a wide field of view (FOV) capable of visualizing biomolecular processes in small animals. This imaging capability is crucial for the development of novel therapies and understanding the progression of disease for a wide range of human conditions like heart disease and cancer. [unreadable] [unreadable] [unreadable]